This invention relates to interleukin-4 (hereinafter called xe2x80x9cIL-4xe2x80x9d) production inhibitors, antiallergic agents and atopic dermatitis preventives and improvers, which contain specific monoterpenes, sesquiterpenes or particular essential oils. This invention is also concerned with bath medicine compositions containing specific plant-derived ingredients.
IL-4 is a substance produced by T lymphocytes which are human or animal immune response cells, and are known to act on B lymphocytes and to enhance production of an antibody such as IgE [Rinsho Meneki (Clinical Immunology), 27, 45-57 (1995)]. For many years IgE is known to take a significant part in the onset of an atopic disease. Further, IL-4 is known to act as an accelerator of inflammatory cell infiltration at lesions in allergic diseases [Cell, 62, 457-467 (1990)]. From these, it is considered that IL-4 is largely implicated in the onset of an allergic disease. Inhibition of IL-4 production, if successfully achieved, is therefore believed to make it possible to treat and prevent allergic diseases more fundamentally from their cause than conventional treatment and preventive methods making use of histamine release inhibitors, IgE or histamine effect inhibitors or the like.
As substances for inhibiting the production of IL-4, a group of sulfonium derivatives including suplatast tosilate is well-known [Japan. J. Pharmacol., 62, 27-30 (1993)]. They are formulated into oral drugs and are used to treat allergic diseases such as atopic dermatitis, itching and pruritus, and the like, but their effects are not sufficient. In addition, their administration routes are limited because they have low percutaneous or transdermal absorption due to their structures. There is hence an outstanding need for IL-4 production inhibitors, antiallergic agents, and atopic dermatitis preventives and improvers, which are excellent in percutaneous or transdermal absorption, stability and safety.
In the case of one having overdrying skin or oversensitive skin and one suffering from atopic dermatitis, on the other hand, the skin is especially sensitive so that the skin tends to develop itching, pruritus, eczema or the like even by mild stimulation. Further, an allergic reaction to a house dust mite antigen, food or the like, psychological stress or the like acts as a deteriorating factor, thereby tending to result in a skin trouble. Use of medicinal bath preparations (JP 2-115117 A), which were added with conventional oil ingredients or humectants, were not able to sufficiently bring about fundamental preventing and improving effects although moistened skin feeling was available temporarily. There is accordingly an outstanding desire for bath medicine compositions, which have high effectiveness for improving skin roughness or dryness and for preventing and improving atopic dermatitis even for those having overdrying or oversensitive skin.
This invention provides use of at least one compound for the production of. an IL-4 production inhibitor, an antiallergic agent or an atopic dermatitis preventive and improver, in which the compound is selected from the group consisting of hydroxyl-containing monoterpenes, hydroxyl-containing sesquiterpenes and acylated derivatives thereof,
This invention also provides use of at least one essential oil for the production of an IL-4 production inhibitor, an antiallergic agent or an atopic dermatitis preventive and improver, in which the essential oil is selected from the group selected from the group consisting of cedarwood oil, eucalyptus oil, patchouli oil, sandalwood oil, vetiver oil, guaiacwood oil, bay oil, clove oil, chamomile oil, ginger oil, cumin oil, pepper oil, rosemary oil, hinoki oil, hiba oil, pimentoberry resinoid and myrrh resinoid.
This invention further provides use of at least one compound for the production of an IL-4 production inhibitor, an antiallergic agent or an atopic dermatitis preventive and improver, in which the compound is selected from the group consisting of eugenol, hinokitiol, cineole and acetylcedrene.
This invention still further provides a method for the treatment of a disease caused by production of IL-4, an allergic disease or atopic dermatitis, which comprises administering at least one essential oil selected from the group consisting of cedarwood oil, eucalyptus oil, patchouli oil, sandalwood oil, vetiver oil, guaiacwood oil, bay oil, clove oil, chamomile oil, ginger oil, cumin oil, pepper oil, rosemary oil, hinoki oil, hiba oil, pimentoberry resinoid and myrrh resinoid.
This invention still further provides a method for the treatment of a disease caused by production of IL-4, an allergic disease or atopic dermatitis, which comprises administering at least one compound selected from the group consisting of eugenol, hinokitiol, cineole and acetylcedrene.
Moreover, the present inventors have found that addition of one or more specific fragrance ingredients out of the above-described ingredients makes it possible to provide a bath medicine composition having high effectiveness for improving symptoms such as skin roughness, dryness, eczema and the like and also skin characteristics prone to skin troubles even for those having overdrying skin or oversensitive skin or suffering from atopic dermatitis.
This invention therefore also provides a bath medicine composition comprising at least one ingredient selected from cedrol, cedrenol, farnesol, patchouli alcohol or vetiverol.
This invention further provides use of at least one ingredient for the production of a bath medicine composition, in which the ingredient is selected from cedrol, cedrenol, farnesol, patchouli alcohol or vetiverol.
Furthermore, the present invention provides a bathing method, which comprises bathing in bathwater added with a composition which comprises at least one ingredient selected from cedrol, cedrenol, farnesol, patchouli alcohol or vetiverol.
Essential oils such as cedarwood oil are found in branches, leaves, roots, stalks, barks, fruits, buds, resins and the like of plants, and owing to the inclusion of abundant volatile ingredients and the possession of characteristic fragrances, are used as ingredients for perfumes. On the other hand, hydroxyl-containing monoterpenes, hydroxyl-containing sesquiterpenes, eugenol, hinokitiol and cineole are found as isolated ingredients of essential oils in branches, leaves and the like of plants. Further, as reaction products of isolated ingredients of essential oils, derivatives such as acetylcedrene and cedryl acetate are used as fragrance ingredients. However, their possession of IL-4 production inhibitory action and the like were not known at all.
Preferred examples of hydroxyl-containing monoterpenes can include l-menthol and citronellole. Preferred examples of hydroxyl-containing sesquiterpenes can include globulol, epiglobulol, farnesol, guaiol, patchouli alcohol, cedrol, santalol, vetiverol, widrrol, thujopsenol and cedrenol. As acylated derivatives, acetylated derivatives are preferred with cedryl acetate being more preferred. Of these, globulol, epiglobulol, farnesol, guaiol, patchouli alcohol, cedryl acetate and cedrol are more preferred, with cedrol being particularly preferred.
Hydroxyl-containing monoterpenes, hydroxyl-containing sesquiterpenes, eugenol, hinokitiol and cineole can be isolated by methods known per se in the art from plants known to contain them. Acetylcedrene, on the other hand, can be obtained by acetylating cedrene which is isolated from cedarwood oil or the like. They may also be chemically synthesized ones.
As these ingredients, known plant extracts, distillate fractions or the like with such ingredients contained therein can be used as they are. Described specifically, essential oils in the form of extracts, resinoids, absolutes or the likexe2x80x94which can be obtained by providing trees, herbs, spices and the like as raw materials and subjecting their wood chips, barks, roots, stalks, leaves, fruits, flowers or the like to extraction, steam distillation, pressing or the like in a manner known per se in the artxe2x80x94can be used as they are. More specifically, it is possible to use, without any further processing or treatment, cedarwood oil as cedrol; eucalyptus oil as globulol or epiglobulol; patchouli oil as patchouli alcohol; bay oil, clove oil or pimentoberry resinoid as eugenol; guiac wood oil as guaiol; hinoki oil as hinokitiol; and cardamon oil or the like as cineole. Illustrative of the above-described trees, herbs, spices and the like are cedar, eucalyptus, patchouli, sandalwood, vetiver, bayberry, clove, chamomile, ginger, cumin, pepper, rosemary, peppermint, valerian, honeysucle, thyme, tea, guaiacwood, hiba, hinoki, pimentoberry, and sage. Concerning these source plants, no particular limitation is imposed on their place of origin, weather, harvesting method, handling method, and the like.
In the present invention, preferred examples of essential oil can include cedarwood oil, eucalyptus oil, patchouli oil, pimentoberry resinoid, vetiver oil, sandalwood oil, bay oil, clove oil, chamomile oil, guaiacwood oil, ginger oil, and cumin oil. Of these, cedarwood oil, eucalyptus oil, patchouli oil, pimentoberry resinoid, vetiver oil and sandalwood oil are more preferred. Still more preferred are cedarwood oil, eucalyptus oil and pimentoberry oil, with cedarwood oil and eucalyptus oil being particularly preferred. Such essential oils can be obtained by methods known per se in the art by using as raw materials plants which contain them.
Such hydroxyl-containing monoterpenes, hydroxyl-containing sesquiterpenes, acylated derivatives thereof, eugenol, hinokitiol, cineole and acetylcedrene, which are useful in the present invention, may have chirality.
Essential oils (hereinafter called xe2x80x9cIL-4 production inhibiting substancesxe2x80x9d), such as these hydroxyl-containing monoterpenes, hydroxyl-containing sesquiterpenes, acylated derivatives thereof, eugenol, hinokitiol, cineole, acetylcedrene, eucalyptus oil and cedarwood oil, have excellent IL-4 production inhibitory activity and are useful for the production of antiallergic agents, especially preventives and improvers for atopic dermatitis, allergic rhinitis and bronchial asthma.
IL-4 is also considered to have some connection to various non-allergic diseases of skin. IL-4 has an effect that it acts on keratinocytes to enhance production of IL-6 [Ann. N.Y. Acad. Sci., 557, 454-465, (1989)], and has been considered to take part in skin inflammation. Further, mast cells stimulated by IL-4 are known to react to endothelin, thereby undergoing a histamine release [J. Immunol., 154, 1830-1837 (1995)]. In view of the fact that endothelin is produced from keratinocytes upon exposure to ultraviolet rays, ultraviolet rays are certainly considered to take part in itching. IL-4 is also known to act on fibroblasts to modify their collagen synthesizing ability [J. Clin. Invest., 90, 1479-1485 (1992)], so that there is possibility that IL-4 may also take part in the development of wrinkles and flabbiness on skin. The IL-4 production inhibitor according to the present invention is therefore expected to be effective for the prevention and treatment of other IL-4-related diseases, namely, itching or pruritus, wrinkles, freckles, dermatophytosis, stomatitis and the like.
The IL-4 production inhibitor, antiallergic agent and atopic dermatitis preventive and improver according to the present invention can be administered as external skin care preparations, oral preparations, injections, inhalants, medicinal bath preparations or the like.
Illustrative of external skin care preparations are ointments, toilet waters, creams, lotions, packs, and foundations. They can be produced by formulating the above-described IL-4 production inhibiting substance, an external skin care base commonly employed in external skin care preparations, one or more other medicinally-effective ingredients and the like in a manner known per se in the art. The external skin care base can be an oil base, an emulsified base of the oil/water or water/oil type, or water. Examples of the oil base can include oils and fats such as vegetable oils and animal oils, higher alcohols, fatty acids, and esters. As illustrative examples of medicinally-effective ingredients, anti-inflammatory analgesics, disinfectants, vitamins, emollients and the like can be used as needed. Further, humectants, ultraviolet absorbers, chelating agents, pH regulators, antiseptics, thickeners, alcohols, colors, perfumes and the like can also be added.
Oral preparations can be obtained by mixing the above-described IL-4 production inhibiting substance with a carrier such as lactose or starch and then forming the resulting mixture into tablets, capsules, granules or powder as needed or by dissolving or dispersing the above-described IL-4 production inhibitor in purified water or the like to provide a liquid preparation, syrup or drink. On the other hand, injections and inhalants can also be prepared by methods known per se in the art.
No particular limitation is imposed on the dose of the above-described IL-4 production inhibitor insofar as it falls within a range commonly adopted for cosmetics, drugs, or quasi-drugs, but a daily dose of from 0.001 to 2000 mg per adult is generally preferred.
For use in the bath medicine composition according to the present invention, one or more ingredients can be selected from cedrol, cedrenol, farnesol, patchouli alcohol and vetiverol. The proportion of such ingredient or ingredients in the bath medicine composition may be 10 ppm or higher, more specifically 0.01 to 20 wt. %, more preferably 1 to 10 wt. % based on all the ingredients. It is preferable to set the one dose of the bath medicine composition such that the concentration of such ingredient or ingredients becomes 0.01 ppm or higher, more specifically 0.1 to 1,000 ppm, more preferably 5.0 to 1,000 ppm in bath water.
In the bath medicine composition according to the present invention, an extract, steam distillate, pressed liquid or the like of a plant containing such an ingredient may also be used.
Examples of such a plant can include cedar, patchouli, and vetiver.
These plants can be subjected to extraction, steam distillation, pressing or the like in a manner known per se in the art. The resulting fraction may be used after fractionating it further or may be used in the form of a further-purified essential oil.
It is particularly preferred to incorporate, in addition to the above-described ingredients, an epidermal lipid or its analogue in the bath medicine composition according to the present invention, because the skin roughness or dryness improving effect can be enhanced further.
Examples of the epidermal lipids and its analogue for use in the present invention can include intercellular corneum lipids such as natural ceramides, ceramide analogues, steroids, fatty acid esters of steroids, fatty acids, and triglycerides; and cerebrosides and phospholipids. Among these, natural ceramides, ceramide analogues, phospholipids and fatty acid esters of steroids are preferred.
As a natural ceramide, it is preferred to use one or more of known type I to type VII which are contained in human epidermal lipids [Hifu Rinsho (Dermatoclinical Medicine), 35, 1147-1161 (1993); Angew. Chem. Int. Ed., 38, 1532-1568 (1999)]. Examples of ceramide analogues can include those represented by the following formulas (1)-(4) and disclosed in JP 63-216812 A [formula (1)], JP 8-319263 A [formula (2)], JP 3-193754 A [formula (3)], JP 4-282304 A [formula (4)] and the like. All of these publications are incorporated herein by reference. 
wherein R1 represents a hydrocarbon group having 10 to 26 carbon atoms, R2 represents a hydrocarbon group having 9 to 25 carbon atoms, and n stands for an integer of from 2 to 6.
In the formula, R1 may preferably be a linear or branched alkyl or alkenyl group having 10 to 26 carbon atoms, with an alkyl group having 10 to 18 carbon atoms being particularly preferred. R2, on the other hand, may preferably be a linear or branched alkyl or alkenyl group having 9 to 25 carbon atoms, with an alkyl group having 9 to 21 carbon atoms being particularly preferred. 
wherein R3 and R4 are the same or different and each independently represent a hydroxylated or unhydroxylated hydrocarbon group having 1 to 40 carbon atoms, R5 represents an alkylene group having 1 to 6 carbon atoms or a single bond, and R6 represents a hydrogen atom, an alkoxy group having 1 to 12 carbon atoms or a 2,3-dihydroxypropyloxy group with a proviso that R6 is a hydrogen atom when R5 is a single bond.
In the formula, R3 may preferably be a linear or branched alkyl or alkenyl group having 8 to 26 carbon atoms, with an alkyl group having 12 to 22 carbon atoms being particularly preferred. R4 may preferably be a linear or branched alkyl or alkenyl group having 9 to 25 carbon atoms, with an alkyl group having 11 to 21 carbon atoms being particularly preferred. R5 may preferably be a linear or branched alkylene group having 1 to 6 carbon atoms, with a linear or branched alkylene group having 1 to 3 carbon atoms being particularly preferred. R6 may preferably be a hydrogen atom, a linear or branched alkoxy group having 1 to 8 carbon atoms, or a 2,3-dihydroxypropyloxy group. 
wherein R7 represents an alkyl or alkenyl group having 11 to 21 carbon atoms, and R8 represents a hydrocarbon group having 3 to 30 carbon atoms.
In the formula, R7 may preferably be an alkyl group having 13 to 17 carbon atoms, and R7 may preferably be a linear or branched alkyl or alkenyl group having 8 to 24 carbon atoms. 
wherein R9 represents a hydroxylated or unhydroxylated, phosphorylated or unphosphorylated, or sulfated or unsulfated aliphatic hydrocarbon group having 1 to 49 carbon atoms, or a fatty acid residual group having 14 to 22 carbon atoms and represented by a substituent groupxe2x80x94(CaHb)xe2x80x94Oxe2x80x94Y in which Y represents a hydrogen atom or an aliphatic hydrocarbon group represented by the following formula: 
wherein Z represents xe2x80x94OH, xe2x80x94OP1, xe2x80x94OSO3xe2x88x92 or an epoxy oxygen, x stands for an integer of from 12 to 20, y stands for an integer of 20 to 40, and z stands for an integer of from 0 to 4, a stands for an integer of from 7 to 49, and b stands for an integer of from 10 to 98; R10 represents a hydroxylated or unhydroxylated, phosphorylated or unphosphorylated, or sulfated or unsulfated aliphatic hydrocarbon group having 1 to 28 carbon atoms; R11 represents a hydrogen atom, a carbohydrate group, a sulfate group or a phosphate group P1 in which P1 represents the following group: 
R12 represents a hydrogen atom or the following substituent group: 
wherein X1, X2 and X3 each independently represent a hydrogen atom or a hydroxylated or unhydroxylated alkyl group having 1 to 5 carbon atoms, c stands for an integer of from 0 to 4, d stands for an integer of 0 or 1, and R11 has the same meaning as defined above; and l and m each independently stand for 0 or 1 with the proviso that l+m is 1 or 2 when R9 has 9 to 49 carbon atoms.
In the formula, R9 may preferably be a linear or branched alkyl or alkenyl group having 6 to 32 carbon atoms, with an alkyl group having 10 to 20 carbon atoms being particularly preferred. R10 may preferably be a linear or branched alkyl or alkenyl group having 8 to 22 carbon atoms, with an alkyl group having 10 to 20 carbon atoms being particularly preferred.
R11 may preferably be a hydrogen atom, and R12 may preferably be a hydroxyethyl group.
Among these, ceramide analogues represented by the formula (1) or (2) are particularly preferred.
Examples of the phospholipids can include those disclosed in JP 3-66604 A, which are presented below by formula (5). This publication is also incorporated herein by reference. 
wherein one of R13 and R14 represents 
and the other represents a hydrogen atom; and X represents: 
Further, preferred examples of the fatty acid esters of the steroids can include cholesteryl fatty acid esters represented by the following formula (6): 
wherein R15 represents a hydroxylated or unhydroxylated hydrocarbon group having 1 to 25 carbon atoms.
The epidermal lipids and their analogues can be used either singly or in combination. They can be added in a proportion of from 0.001 to 60 wt. %, especially from 0.01 to 20 wt. % based on all the ingredients. It is preferred to set the one dose of the bath medicine composition such that their concentration becomes 0.01 ppm or higher, especially ranges from 0.1 to 1,000 ppm in bath water, because this concentration gives excellent feeling of use.
The bath medicine composition according to the present invention can also be added with another oil ingredient and a surfactant. These oil ingredient and surfactant make it possible to provide a self-emulsifying bath medicine composition which makes bath water cloudy and gives good feeling of use.
As the oil ingredient, it is preferred to use one or more compounds selected from glycerides, oils and fats, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters and silicone oils. As the glycerides, diglycerides are preferred, with diglycerides such as the diglyceryl esters of one or more fatty acids, for example, 2-ethylhexanoic acid, myristyl acid, oleic acid and isostearic acid being particularly preferred. Illustrative of the oils and fats are natural oils and fats, such as soybean oil, rice bran oil, jojoba oil, avocado oil, almond oil, olive oil, cacao butter, sesame oil, persic oil, castor ol, coconut oil, mink oil, beef tallow and lard; hardened oils obtained by hydrogenating these natural oils and fats; and synthetic triglycerides such as glycerol myristate and glycerol tri-2-ethylhexanoate. Illustrative of the waxes are carnauba wax, whale wax and beeswax. Illustrative of the hydrocarbons are liquid paraffin, vaseline, paraffin microcrystalline wax, seresine, squalane, and pristane. Illustrative of the higher fatty acids are lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, lanolin acid, and isostearic acid. Illustrative of the higher alcohols are lauryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, lanolin alcohol, and 2-hexyldecanol. Illustrative of the esters are myristyl lactate, cetyl lactate, isopropyl myristate, myristyl myristate, isopropyl palmitate, isopropyl adipate, butyl stearate, and decyl oleate. Illustrative of the silicone oils are dimethylpolysiloxane, and various silicones.
These oil ingredients can be used either singly or in combination. It is preferred to add them in a proportion of from 0.01 to 99 wt. %, especially from 50 to 95 wt. % based on the whole composition.
As the surfactant, on the other hand, nonionic, cationic, anionic and amphoteric surfactants are all available no matter whether they are natural surfactants or synthetic surfactants. Illustrative nonionic surfactants can include polyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, fatty acid monoglycerides, sugar fatty acid esters, and higher fatty acid alkanols. Typical cationic surfactants can be quaternary ammonium salts. Quaternary ammonium salts can all be used preferably insofar as they are generally available for the body, and those containing the branched quaternary ammonium salts disclosed in JP 61-267505 A are preferred. Illustrative anionic surfactants can include alkyl- or alkenylsulfate salts, alkyl- or alkenylsufate salts added with ethylene oxide and/or propylene oxide, olefinsulfonate salts, alkanesulfonate salts, saturated or unsaturated fatty acid salts, alkyl- or alkenylether carboxylate salts added with ethylene oxide and/or propylene oxide, xcex1-sulfofatty acid salt esters, surfactants of the amino acid type, surfactants of the phosphate ester type, surfactants of the sulfosuccinic acid type, surfactants of the taurin type, and surfactants of the amide ether sulfate type. Illustrative amphoteric surfactants can include amphoteric surfactants of the sulfonic acid type and amphoteric surfactants of the betaine type.
These surfactants can be used either singly or in combination. It is preferred to add them in a proportion of from 0.01 to 90 wt. %, especially from 5 to 20 wt. % based on the whole composition.
To the bath medicine composition according to the present invention, ingredients employed in general bath medicine compositions, for example, inorganic salts, organic acids, vegetable and animal drugs, other essential oils, other perfumes, colors, vitamins, polyhydric alcohols, fine-powders, sulfur, deposits of hot-spring water, antiseptics and the like can be added as needed to extents not impairing the effects of the present invention.
To the bath medicine composition according to the present invention, water can be added in an appropriate proportion within a range of from 0.01 to 90 wt. % to increase the stability of the composition or to form the composition into an emulsified form.
The bath medicine composition according to the present invention can be formulated into a desired preparation form such as powder, granules, tablets, capsules, a liquid, or an emulsion by a method known per se in the art. Further, the one dose of the bath medicine composition according to the present invention can be varied as desired, and may range preferably from 1 to 500 g, especially from 5 to 100 g for general home bathtubs of from 150 to 200 liters